2532

OBJECTIVES/SPECIFIC AIMS: The central goal is to predict the metabolites of varenicline and predictively evaluate their propensities for eliciting an increased binding effect in the brain. METHODS/STUDY POPULATION: Molecular modeling computational software and other cheminformatic tools present a strategic in silico strategy to predict a complete metabolic transformation for the varenicline molecule. Molecular docking tools help to highlight key interactions of the varenicline with key metabolizing enzymes that are differentially expressed across a population. This will assist in validating clinical models for smoking cessation. RESULTS/ANTICIPATED RESULTS: Differentialized binding results depending on whatever metabolite is produced. DISCUSSION/SIGNIFICANCE OF IMPACT: Products of metabolism of varenicline may differ in individuals and across groups, thus, binding effects and the propensity for adverse effects may differ in individuals.

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Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽

10.3390/biom11060909 ◽

2021 ◽

Vol 11 (6) ◽

pp. 909

Author(s):

Yurii A. Zolotarev ◽

Vladimir A. Mitkevich ◽

Stanislav I. Shram ◽

Alexei A. Adzhubei ◽

Anna P. Tolstova ◽

...

Keyword(s):

Molecular Modeling ◽

Mouse Model ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Laboratory Animals ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Bolus Administration ◽

Blood Brain ◽

The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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Molecular Modeling Studies on 2,4-Disubstituted Imidazopyridines as Anti-Malarials: Atom-Based 3D-QSAR, Molecular Docking, Virtual Screening, In-Silico ADMET and Theoretical Analysis

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521500125 ◽

2021 ◽

pp. 2150012

Author(s):

Suraj N. Mali ◽

Anima Pandey

Keyword(s):

Molecular Docking ◽

Molecular Modeling ◽

Virtual Screening ◽

In Silico ◽

Energy Gap ◽

3D Qsar ◽

Modeling Studies ◽

In Vitro Investigation ◽

In Silico Admet ◽

Molecular Modeling Studies

Malarial parasites have been reported for moderate-high resistance towards classical antimalarial agents and henceforth development of newer novel chemical entities targeting multiple targets rather than targeting single target will be a highly promising strategy in antimalarial drug discovery. Herein, we carried out molecular modeling studies on 2,4-disubstituted imidazopyridines as anti-hemozoin formation inhibitors by using Schrödinger’s molecular modeling package (2020_4). We have developed statistically robust atom-based 3D-QSAR model (training set, [Formula: see text]; test set, [Formula: see text]; [Formula: see text] [Formula: see text]; root-mean-square error, [Formula: see text]; standard deviation, [Formula: see text]). Our molecular docking, in-silico ADMET analysis showed that dataset molecule 37, has highly promising results. Our ligand-based virtual screening resulted in top five ZINC hits, among them ZINC73737443 hit was observed with lesser energy gap, i.e. 7.85[Formula: see text]eV, higher softness value (0.127[Formula: see text]eV), and comparatively good docking score of [Formula: see text]10.2[Formula: see text]kcal/mol. Our in-silico analysis for a proposed hit, ZINC73737443 showed that this molecule has good ADMET, in-silico nonames toxic as well as noncarcinogenic profile. We believe that further experimental as well as the in-vitro investigation will throw more lights on the identification of ZINC73737443 as a potential antimalarial agent.

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Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors

Molecules ◽

10.3390/molecules27020387 ◽

2022 ◽

Vol 27 (2) ◽

pp. 387

Author(s):

Xiangcong Wang ◽

Moxuan Zhang ◽

Ranran Zhu ◽

Zhongshan Wu ◽

Fanhong Wu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Modeling ◽

3D Qsar ◽

Binding Mode ◽

Biological Evaluation ◽

Field Analysis ◽

Dynamics Simulation ◽

Comfa Model ◽

Qsar Models

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).

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Proteome-Wide Mapping and Reverse Vaccinology Approaches to Design a Multi-Epitope Vaccine against Clostridium perfringens

Vaccines ◽

10.3390/vaccines9101079 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1079

Author(s):

Fahad M. Aldakheel ◽

Amna Abrar ◽

Samman Munir ◽

Sehar Aslam ◽

Khaled S. Allemailem ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Epitope Vaccine ◽

Ifn Gamma ◽

Cellular Immune Responses ◽

Medical Control ◽

Food Borne ◽

Food Borne Illness ◽

Cellular Immune ◽

The Brain

C. perfringens is a highly versatile bacteria of livestock and humans, causing enteritis (a common food-borne illness in humans), enterotoxaemia (in which toxins are formed in the intestine which damage and destroy organs, i.e., the brain), and gangrene (wound infection). There is no particular cure for the toxins of C. perfringens. Supportive care (medical control of pain, intravenous fluids) is the standard treatment. Therefore, a multiple-epitope vaccine (MEV) should be designed to battle against C. perfringens infection. Furthermore, the main objective of this in silico investigation is to design an MEV that targets C. perfringens. For this purpose, we selected the top three proteins that were highly antigenic using immuno-informatics approaches, including molecular docking. B-cells, IFN-gamma, and T cells for target proteins were predicted and the most conserved epitopes were selected for further investigation. For the development of the final MEV, epitopes of LBL5, CTL17, and HTL13 were linked to GPGPG, AAY, and KK linkers. The vaccine N-end was joined to an adjuvant through an EAAK linker to improve immunogenicity. After the attachment of linkers and adjuvants, the final construct was 415 amino acids. B-cell and IFN-gamma epitopes demonstrate that the model structure is enhanced for humoral and cellular immune responses. To validate the immunogenicity and safety of the final construct, various physicochemical properties, and other properties such as antigenicity and non-allergens, were evaluated. Furthermore, molecular docking was carried out for verification of vaccine compatibility with the receptor, evaluated in silico. Also, in silico cloning was employed for the verification of the proper expression and credibility of the construct.

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Drug metabolizing enzymes in the brain and cerebral microvessels

Brain Research Reviews ◽

10.1016/0165-0173(91)90020-9 ◽

1991 ◽

Vol 16 (1) ◽

pp. 65-82 ◽

Cited By ~ 125

Author(s):

Alain Minn ◽

Jean-François Ghersi-Egea ◽

Rachel Perrin ◽

Brigitte Leininger ◽

Gérard Siest

Keyword(s):

Drug Metabolizing Enzymes ◽

Metabolizing Enzymes ◽

Cerebral Microvessels ◽

The Brain

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Molecular Modeling Study for the Evaluation of Natural Compounds as Potential Lanosterol 14α-demethylase Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180818666211027114007 ◽

2021 ◽

Vol 18 ◽

Author(s):

Nidhi Rani ◽

Randhir Singh ◽

Praveen Kumar

Keyword(s):

Molecular Docking ◽

Molecular Modeling ◽

Fungal Infections ◽

Docking Study ◽

Natural Compounds ◽

Docking Studies ◽

Prosthetic Group ◽

Fungal Cell ◽

Adme Profile ◽

Target Enzyme

Background: Candida albicans is one of the most important causes of fatal fungal infections. Ergosterol, the main sterol in the fungal cell membrane, is the resultant product of Lanosterol in the presence of the enzyme Lanosterolα-demethylase (Cytochrome P450DM). This enzyme is the target enzyme of azole antifungal agents. Aim: To evaluate the antifungal potency of some of the natural compounds via molecular modeling and Absorption, Distribution, Metabolism and Excretion (ADME) study. Method: The study involved the selection and modeling of the target enzyme, followed by the refinement of the model using molecular dynamic simulation. The modelled structure of the enzyme was validated using the Ramachandran plot and Sequence determination technique. A series of natural compounds was evaluated for cytochrome P450 inhibitory activity using molecular docking studies. The structures of compounds were prepared using a Chem sketch, and molecular docking was performed using Molergo Virtual Docker (MVD) program. Results: The docking study indicated that all the natural compounds have interactivity with protein residue of 14α-demethylase, and the heme prosthetic group and water molecules are present at the active site. The data were also correlated with the synthetic compounds that were experimentally inactive against the fungus and had a low docking score. The compounds with a high dock score were further screened for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile, and it was predicted that these compounds can be used as lead with a good ADME profile and low toxicity. Conclusion: The natural compound, i.e., curcumin, can easily be used further for lead optimization.

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Abstract 2381: Aneurysmal Subarachnoid Hemorrhage: Metabolic and Blood Flow Patterns

Circulation ◽

10.1161/circ.116.suppl_16.ii_522 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

parham moftakhar ◽

Thomas C Glenn ◽

John Boscardin ◽

Neil A Martin

Keyword(s):

Blood Flow ◽

Phase Ii ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Phase Iii ◽

Entire Study ◽

Cerebral Metabolic Rate ◽

Study Population ◽

Blood Flow Patterns ◽

The Brain ◽

Oxygen Difference

Objective: The purpose of this study is to classify and describe the clinically distinct metabolic and hemodynamic phases post-ASAH. Methods: 224 patients who suffered an ASAH (mean age 55±14; 74% female, 26% male) were examined. Patients underwent daily transcranial Doppler (TCD) and cerebral blood flow (CBF) studies (using 133 Xe clearance). Due to the paucity of data on post-hemorrhage day (PHD) 0, the internal carotid artery end-diastolic (ICA ED ) velocity, a surrogate for CBF, was used for the first 24 hours. The brain arteriovenous oxygen difference (AVDO 2 ) was recorded for each patient and the cerebral metabolic rate of oxygen (CMRO 2 ) was calculated. Clinical outcome was evaluated based on the Glasgow Outcome Scale (GOS) 6 months after rupture. Results: Following ASAH, 3 distinct hemodynamic phases arose for the entire study population. Phase I (hypoperfusion phase), occurs on the day of rupture (PHD 0) and is defined by a low ICA ED velocity (mean 17.8±1.1 cm/s), normal middle cerebral artery (MCA) velocity (mean V MCA 58.0±23.4 cm/s), and normal Lindegaard Ratio ([LR], mean 1.66±0.50). Phase II (relative hyperemia), (PHD 1–3), is characterized by an increasing ICA ED (mean 35.4±1.0 cm/s, p<0.0001), a relative hyperemia (mean CBF 15 40.1±1.5 ml/100g/minute, CMRO 2 1.17±0.41 ml/100g/min), a rising V MCA (mean 71.5±5.8 cm/sec, p<0.0001), and a rising but normal LR (mean 2.21±0.19, p<0.0001). During phase III (vasospasm phase, PHD 4–21), both the ICA ED and CBF decrease (mean ICA ED 19.9±0.9 cm/s, p<0.0001; mean CBF 15 36.8±0.7 ml/100g/minute, p=0.04), V MCA continues to rise (mean 107.6±2.9cm/sec, p<0.0001), and the LR is further increased (mean 3.25±0.08, p<0.0001). The CMRO 2 remains low (mean 1.17±0.40 ml/100g/min, p=1). Based on the GOS up to 90% of patients who experienced either a relative or absolute hyperemia had good outcomes. Conclusions: After an ASAH, 3 discrete metabolic and hemodynamic phases arise each with the potential for its own unique phase-specific management and therapy. Relative hyperemia, or “luxury perfusion,” during Phase II in the setting of non-elevated ICPs may provide some type of benefit for patients.

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